The present invention relates to a radioactive or activatable seed used for brachytherapy, in particular for restenosis treatment and tumour therapy. The invention further relates to a method for producing said radioactive or activatable seed.
Radiation therapy is a well-established method for treating various types of illnesses including cancers such as prostate cancer and mamma carcinoma. Presently, such radiation therapy is typically carried out by using miniature medical radiation sources, so-called seeds, either by employing individual seeds or a multitude of seeds, e.g. a xe2x80x9ctrain of seedsxe2x80x9d. Such seeds have also been used subsequent to treatment of arteriosclerosis and arthrosclerosis by balloon angioplasty in order to prevent restenosis due to the growth of scar tissue. All of these therapy forms are herein addressed as brachytherapy.
Brachytherapy targets the tissue adjacent to the radiation source while keeping the radiation effects on surrounding healthy tissue to a minimum. A major advantage of this form of treatment is therefore that it concentrates the emitted radiation at the site where the treatment is needed, while keeping the amount of radiation transmitted to the healthy tissue far below what it otherwise would be, if the radiation were beamed into the body from an external source using teletherapy.
Radiation brachytherapy is normally practiced in one of three ways: (1) By placing the source or sources within the tissue to be treated, i.e. interstitial therapy (e.g. mamma carcinoma); (2) by placing the source or sources inside a body cavity normally in association with the positioning device to irradiate the tissue surrounding the cavity, i.e. intracavitary therapy (e.g. prostate cancer); or (3) by placing the source or sources within a vessel or duct, normally in association with a catheter, to treat the tissue surrounding the vessel or duct, i.e. intraluminal therapy (e.g. restenosis).
Typically the radiation sources for brachytherapy are either introduced or implanted for short terms and are later removed from the body or are implanted for a longer term and may even remain permanently in the patient after treatment. The implanted sources or seeds typically comprise a radionuclide absorbed on or distributed throughout a carrier which is positioned inside a non-radioactive and preferably non-activatable biocompatible casing such as a welded metal tube. For monitoring purposes the seeds may further comprise radio-opaque markers within the casing. Such radio-opaque markers comprise high Z elements and are arranged within the casing in association with or separated from the carrier of the chosen isotope.
Prior art casings function as non-radioactive diffusion barriers that prevent migration of radioactive particles into the surrounding tissue. They further provide sufficient mechanical stability, biocompatibility and corrosion-resistance to the seed. Since the casing material absorbs radiation to a certain extent, the amount of radioactive material which is positioned inside the casing has to be increased to allow for the desired emission to be achieved. To minimize this effect the casing thus typically comprises a low shielding material such as Ti and/or Al.
Sources of high radiation intensity including nuclides such as Ra-226, Cs-137 or Au-198 have been and are still used. The most commonly used radionuclides for brachytherapy are, however, iodine 125 and palladium 103 due to their radiation spectrum, dosages and halflives. For example, U.S. Pat. No. 3,351,049 describes seeds with an encapsulating outer shell containing the radiation-emitting isotopes 1-125 or Pd-103. In these seeds an encapsulation shell localizes the radioactivity by physically preventing the radionuclide from migrating to other parts of the body.
U.S. Pat. Nos. 4,994,013 and 5,163,896 disclose a pellet for radioactive seeds, suitable for use in certain medical radiological treatments, comprising a metallic X-ray detectable marker rod coated with a polymeric material wherein or on which the radioactive material is adsorbed. The pellets are encapsulated in a material such as titanium to form an effectively sealed radioactive seed.
WO 97/19706 discloses a radioactive composite for use in therapeutic applications such as brachytherapy consisting essentially of a polymeric material and fine radioactive particles that are dispersed within the polymeric material. Compared to metallic casings or shells polymeric materials disclosed in WO 97/19 706 have a reduced stability towards mechanical strain or activation procedures and are less resistant to body fluids. According to WO 97/19 706 the radioactive composite can even be disintegrated e.g. by biodegradation in the patient""s body after a predetermined period.
WO 86/04 248 discloses Pd-103 particles or seeds that are manufactured for implantation into turnours within a human body for emitting X-rays to destroy or reduce the tumors. The seeds contain palladium which is substantially enriched in palladium-102 and which is activated by exposure to neutron flux so as to contain X-ray emitting Pd-103. The palladium is distributed in or throughout a base material. The base material is then in turn encased in an elongated shell which is non-radioactive and non-activatable.
European patent application EP-A-I,OO8,995 discloses a radioactive palladium-103 miniature radiation source (seed) wherein the carrier matrix consists of a porous and mechanically stable inorganic material, the pores of which contain Pd-103 as a metal or in the form of a stable and water-insoluble Pd-103 compound. Preferred and exemplified are ceramic matrices. Mandatory to the seed disclosed is the porous nature of the matrix which is necessary for absorbing by capillary forces the solution comprising a soluble Pd-103 compound. After absorption the soluble Pd-103 is converted to its final insoluble form. The active carrier matrix is then encapsulated in a corrosion-resistant and body-compatible material, the encapsulating material itself being non-radioactive.
In general, there are two possibilities for producing radioactive devices. The first method refers to the use of radioactive material, i.e. material being radioactive throughout at least in part of the manufacturing process. This method is commonly called xe2x80x9chotxe2x80x9d assembly. In practice, additional safety measures are necessary to avoid any direct contact with or contamination by the radioactive material. This method is mandatory for naturally occurring radioactive nuclides, nuclides obtained as fission products from nuclear fission and radionuclides which cannot be obtained from inactive precursors via a later activation step such as neutron bombardment.
Alternatively an activatable material, i.e. a material which can be converted to a radioactive material, is used and activation occurs subsequent to complete assembly. This method is called xe2x80x9ccoldxe2x80x9d assembly. Cold assembly typically requires careful choice of seed materials with respect to stability during activation and generation of radioactive impurities.
Following the above discussion most of the prior art brachytherapy devices use non-radioactive and non-activatable (in that they do not activate to produce undesirable impurities) biocompatible metallic casings resistant to mechanical strain and body fluids, typically Ti. However, since these materials absorb radioactive radiation to a certain extent i.e. exert a shielding effect to the emitted radiation, all these devices need an increased amount of radioactive or activatable material inside the casing to allow for emission of a desired therapeutically effective radiation dose and thus to produce a desired therapeutic effect. Another disadvantage is that the shielding effect strongly depends on geometry and thickness of the casing.
It is therefore an object of the present invention to overcome these drawbacks and, in particular, to provide a radiation source for radiation therapy (seed), especially for tumor therapy and restenosis treatment, with a reduced amount of radioactive material producing a sufficient therapeutic effect, which seed is also resistant to mechanical strain and body fluids.
Furthermore, it is an object of the present invention to provide a method for producing such a radiation source.
These objects are solved by the radioactive or activatable seed and the method of producing this seed.
More in detail, according to the present invention there is provided a radioactive or activatable seed comprising a closed and self-supported casing consisting of (a) a radioactive or activatable metallic material selected from the group consisting of a metal, an alloy and a metal composite or mixtures thereof, optionally in combination with (b) a non-radioactive, non-activatable metallic material; wherein (a) comprises a radioactive nuclide selected from the group consisting of Pd-103, Tm-170, Sr-90, Y-90, Yb-169, P-32, Ge-71, Se-75, Cl-36, Ta-182, Tl-204, Re-188, W-188, Ce-144, Pr-144, Sn-123, Ru-106, Rh-106 and mixtures thereof, and/or an activatable precursor nuclide thereof selected from the group consisting of Pd-102, Rh-103, Tm-169, Y-89, Yb-168, P-31, Ge-70, Se-74, Cl-35, Ta-181, Tl-203, W-186, Sn-122 and mixtures thereof, excluding metallic Pd with natural abundance of Pd-102.
According to another embodiment of the present invention there is provided a method of preparation of a radioactive or activatable seed comprising the steps of:
a) providing the body of a closed and self-supported casing consisting of (a) a radioactive or activatable metallic material selected from the group consisting of a metal, an alloy and a metal composite or mixtures thereof, optionally in combination with (b) a non-radioactive, non-activatable metallic material; wherein (a) comprises a radioactive nuclide selected from the group consisting of Pd-103, Tm-170 Sr-90 Y-90 Yb-169 P-32 Ge-71 Se-75 Cl-36 Ta-182 Tl-204 Re-188, W-188, Ce-144, Pr-144, Sn-123, Ru-106, Rh-106 and mixtures thereof, and/or an activatable precursor nuclide thereof selected from the group consisting of Pd-102, Rh-103, Tm-169, Y-89, Yb-168, P-31, Ge-70, Se-74, Cl-35, Ta-181, Tl-203, W-186, Sn-122 and mixtures thereof, excluding metallic Pd with natural abundance of Pd-102;
b) optionally inserting a radio-opaque marker and/or a filler;
c) closing the casing; and
d) optionally providing one or more coating(s).